rs779809838

Positions:

• chr11-46320289-C-A
• chr11-46320289-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_052854.4(CREB3L1):​c.1284C>A​(p.Tyr428Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CREB3L1 NM_052854.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.778

Genes affected

CREB3L1 (HGNC:18856): (cAMP responsive element binding protein 3 like 1) The protein encoded by this gene is normally found in the membrane of the endoplasmic reticulum (ER). However, upon stress to the ER, the encoded protein is cleaved and the released cytoplasmic transcription factor domain translocates to the nucleus. There it activates the transcription of target genes by binding to box-B elements. [provided by RefSeq, Jun 2013]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-46320289-C-A is Pathogenic according to our data. Variant chr11-46320289-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 559484.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CREB3L1	NM_052854.4	c.1284C>A	p.Tyr428Ter	stop_gained	11/12	ENST00000621158.5	NP_443086.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CREB3L1	ENST00000621158.5	c.1284C>A	p.Tyr428Ter	stop_gained	11/12	1	NM_052854.4	ENSP00000481956	P1
CREB3L1	ENST00000616094.1	n.878C>A		non_coding_transcript_exon_variant	3/4	1
CREB3L1	ENST00000534616.5	n.755C>A		non_coding_transcript_exon_variant	3/3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Osteogenesis imperfecta type 16 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Benign	0.036
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.33	N
MutationTaster	Benign	1.0	A;A
Vest4		0.90
GERP RS		-1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs779809838; hg19: chr11-46341840;